Biomedical subjects

B B Davis

Publications and source records attributed to B B Davis.

At least 91 records · Page 5Linked to original sources

PubMed1986

Eicosanoid synthesis by cultured human urothelial cells: potential role in bladder cancer.

Prostaglandin (PG) H synthase and eicosanoid products of arachidonic acid metabolism have been implicated in several steps in the carcinogenic process. This study assessed these parameters using primary cultures of human urothelial cells. To determine the possible presence of permeability barriers to agonist stimulation, incubations were performed with adherent cells in the presence or absence of thioglycolate pretreatment or with cell suspensions. No evidence for permeability barriers was observed. With adherent cells in the absence of thioglycolate, radioimmunoassayable PGE2 was stimulated by epinephrine less than 12-O-tetradecanoylphorbol-13-acetate = thrombin less than bradykinin = A23187 much less than arachidonic acid. Tumor promoters but not non-tumor promoters stimulated PGE2 synthesis. 1-Oleoyl-2-acetylglycerol which like 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C also increased PGE2 synthesis. Cells prelabeled with [14C]arachidonic acid were exposed to agonists and the profile of eicosanoids synthesized was assessed by high performance liquid chromatography. With bradykinin, the pattern of eicosanoids synthesized was 6-keto-PGE1 alpha (12% of total 14C label), thromboxane B2 (0.4%), PGF2 alpha (1.7%), PGE2 (18%), PGD2 (1%), leukotrienes (0.4 to 1%), 12-hydroxy-5,8,10-heptadecatrienoic acid (3%), 15-hydroxy-5,8,11,13-eicosatetraenoic acid (4%), 12-hydroxy-5,8,10,14-eicosatetraenoic acid (0%) and 5-hydroxy-5,8,12,14-eicosatetraenoic acid (2%). Thus, human urothelial cells contain both prostaglandin H synthase and lipoxygenase pathways with the former being more prominent. These pathways may participate in urinary bladder carcinogenesis.

Arachidonic Acids↗

PubMed1986

Aging and the kidney.

Numerous anatomic and physiologic alterations occur in the kidney with aging. These changes affect the ability of elderly patient(s) to maintain homeostasis and alter response to medications, stress, illness, or changes in diet, mobility, or environment. Drug-induced illness and drug interactions are major problems in the elderly. Bone disease and fractures are associated with negative calcium balance and decreased production of 1,25-dihydroxycholecalciferol seen with aging. The geriatric patient is not immune to the primary glomerular diseases that occur in younger patients, although the relative incidence of pathologic diagnoses may differ. The high incidence of membranous glomerulonephritis in the elderly, and the well-known association between malignancy and membranous nephropathy strongly favor aggressive evaluation of the nephrotic syndrome in the geriatric age group. Attention must be given to consideration of appropriate end-stage renal disease treatment alternatives for the geriatric population, which now comprises the fastest-growing segment of the end-stage renal disease population.

Adult↗

PubMed1985

Effect of phosphodiesterase inhibitors on bradykinin-mediated prostaglandin E2 and cyclic AMP synthesis in renal papillary collecting tubule cells.

Isolated rabbit renal papillary collecting tubule cells were used to examine the effects of phosphodiesterase inhibitors on intracellular cyclic AMP and prostaglandin synthesis. Experiments performed on confluent primary tissue cultures demonstrated that bradykinin increases intracellular cyclic AMP by a prostaglandin-dependent mechanism. Phosphodiesterase inhibitors induced a dose-dependent decrease in bradykinin-stimulated prostaglandin synthesis. Fifty percent inhibition occurred with approximately 0.7 mM 3-isobutyl-1-methylxanthine (IBMX). Inhibition was found to be reversible. IBMX did not inhibit bradykinin-induced prostaglandin synthesis as a result of increased intracellular cyclic AMP. The nonmethylxanthine phosphodiesterase inhibitor RO 20-1724 also reduced bradykinin-stimulated prostaglandin synthesis. IBMX inhibited calcium-ionophore-A23187-induced prostaglandin synthesis but did not inhibit arachidonic acid stimulation of prostaglandin synthesis. The data demonstrate that bradykinin increased renal papillary collecting tubule cell cyclic AMP in a prostaglandin-dependent manner. Based on the data presented, phosphodiesterase inhibitors act to decrease arachidonic acid availability for prostaglandin synthesis, independent of changes in cellular cyclic AMP content.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Prostaglandin H synthase oxidation of benzidine and o-dianisidine: reduction and conjugation of activated amines by thiols.

Prostaglandin H synthase oxidized the carcinogens benzidine and o-dianisidine to their respective quinonediimines. Analysis of the reaction media by u.v./visible spectroscopy and liquid chromatography with electrochemical and radiochemical detection revealed that these quinonediimines can be both conjugated and reduced by glutathione, cysteine and N-acetylcysteine. Analysis of the purified conjugate formed between synthetic benzidinediimine and glutathione by proton magnetic resonance spectroscopy demonstrated the product to be 3-(glutathion-S-yl)-benzidine. This metabolite was also formed during peroxidation of benzidine by prostaglandin H synthase in the presence of excess glutathione. These conjugates may be useful markers of peroxidatic activation of aromatic amines in vivo.

Amines↗

PubMed1985

Formation of thioether conjugates of the bladder carcinogen ANFT catalyzed by prostaglandin H synthase.

Certain 2-aminothiazole-substituted 5-nitrofuran carcinogens specifically and potently induce tumors of the urinary tract. Cooxidation by the hydroperoxidase activity of prostaglandin H synthase (PHS) has been implicated in the initiation of this process in vivo. The molecular mechanism of this process was examined utilizing 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) as the organic cosubstrate. The ability of ANFT to release electrons was determined by cyclic voltammetry, which established that ANFT is oxidized to yield an extremely reactive intermediate by an apparent one-electron mechanism. In conventional incubations containing solubilized microsomal PHS at pH 7.8, glutathione was found to trap approximately 50% of the ANFT present as a soluble metabolite. Comparative u.v. spectrophotometry, cyclic voltammetry, proton and carbon magnetic resonance spectroscopy, and chemical synthesis established that conjugate formation occurs by S-substitution of the thiazole ring to yield 2-amino-4-(5-nitro-2-furyl)-5-(glutathion-S-yl)thiazole. The 5-nitrofuran ring is not altered by this pathway. This suggests that PHS may oxidize the aminothiazole ring of ANFT by direct electron withdrawal to generate a reactive electrophilic intermediate which may react with critical cellular nucleophiles. This conjugate, or a further metabolite thereof, may be a biologic marker of PHS activity and may be useful in assessing the effects of potential chemoprotective agents on hydroperoxidase activity in vivo.

Chromatography, Liquid↗

PubMed1985

Role of renal metabolism and excretion in 5-nitrofuran-induced uroepithelial cancer in the rat.

5-Nitrofurans have been used in the study of chemical carcinogenesis. There is substantial evidence that N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) is deformylated to 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in the process of FANFT-induced bladder cancer. Paradoxically, ANFT is less potent as a uroepithelial carcinogen than FANFT when fed to rats. Feeding aspirin with FANFT to rats decreases the incidence of bladder cancer. Isolated kidneys were perfused with 5-nitrofurans to determine renal clearances and whether aspirin acts to decrease urinary excretion of the carcinogen. In FANFT-perfused kidneys, FANFT was deformylated to ANFT and excreted (1.06 +/- 0.22 nmol/min) at a rate eightfold higher than excretion of FANFT. In kidneys perfused with equimolar ANFT, excretion of ANFT was 0.25 +/- 0.05 nmol/min, which suggests a coupling of renal deformylation of FANFT to excretion of ANFT in FANFT-perfused kidneys. Neither aspirin nor probenecid altered the urinary excretion or half-life of FANFT or ANFT. In rats fed 0.2% FANFT as part of their diet, coadministration of aspirin (0.5%) increased urinary excretion of ANFT during a 12-wk feeding study, which suggests decreased tissue binding or metabolism of ANFT. Kidney perfusion with acetylated ANFT (NFTA), a much less potent uroepithelial carcinogen, resulted in no ANFT excretion or accumulation, which indicates the specificity of renal deformylase. Renal deformylase activity was found in broken cell preparations of rat and human kidney. These data describe a unique renal metabolic/excretory coupling for these compounds that appears to explain the differential carcinogenic potential of the 5-nitrofurans tested. These results are consistent with the hypothesis that aspirin decreases activation of ANFT by inhibiting prostaglandin H synthase.

Administration, Oral↗

PubMed1985

Renal reduced nicotinamide adenine dinucleotide phosphate:cytochrome c reductase-mediated metabolism of the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide.

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) metabolism was examined in vitro using microsomes prepared from rat liver and renal cortex and from rabbit liver and renal cortex and outer and inner medulla. NFTA nitroreduction was observed with each tissue. Three mol of NADPH were used per mol of NFTA reduced. Substrate and inhibitor specificity suggested that the microsomal nitroreduction was due to NADPH:cytochrome c reductase. Metabolite(s) formed bound to protein, RNA, DNA, and synthetic polyribonucleotides. Maximum covalent binding was seen with polyguanylic acid. A guanosine-NFTA adduct was isolated. Binding was inhibited by sulfhydryl compounds and vitamin E. The [14C]NFTA:glutathione or [3H]glutathione:NFTA conjugates obtained from microsomal incubations showed identical chromatographic properties as the product obtained by the reaction of synthetic N-hydroxy-NFTA with [3H]glutathione. Structures of synthetic N-hydroxy-NFTA and the microsomal reduction product 1-[4-(2-acetylaminothiazolyl)]-3-cyano-1-propanone were established by mass spectrometry. The latter reduction product did not bind macromolecules. These results suggest that renal NADPH:cytochrome c reductase reduces NFTA to an N-hydroxy-NFTA intermediate that binds nucleophilic sites on macromolecules.

Animals↗

PubMed1984

Mass spectrometry of 2-substituted-4-arylthiazoles. 3--Identification of microsomal nitroreduction products by mass spectrometry.

The electron impact mass spectra of the chemical carcinogens 4-(4-nitrophenyl)-2- methylaminothiazole , 4-(4-aminophenyl)-2- methylaminothiazole and 4-(4-aminophenyl)-2- aminothiazole were studied. The 4-(4-amino-phenyl)-2-substituted thiazoles were isolated from the anaerobic microsomal reduction of their respective 4-nitrophenyl analogues. Microsomes prepared from rat and rabbit kidney tissues were used. The identity of the reduction products were established by chemical synthesis and mass spectrometry. The mass spectrometric fragmentation of the nitro derivative shows prominent ions arising from the loss of the nitro group, ring enlargement of the thiazoles, and the phenylthiirene ion resulting from 1,2-cleavage of the thiazole ring. In the 4-(4-aminophenyl)-2-substituted amino derivative prominent ions result from the preferential 1,2-cleavage of the thiazole ring to give the common 2-(4-aminophenyl) thiirene ion and subsequent fragmentation of this ion.

Aniline Compounds↗

PubMed1984

Enzyme systems involved in the formation of reactive metabolites in the renal medulla: cooxidation via prostaglandin H synthase.

Metabolism of drugs and xenobiotics by renal mixed-function oxidases and prostaglandin H synthase was examined. Significant mixed-function oxidase activity was observed in the cortex and outer medulla. However, mixed-function oxidase activity was not detected in the inner medulla. In contrast, prostaglandin H synthase is quite active in the inner and outer medulla with no detectable activity in the cortex. Prostaglandin H synthase was shown to activate a variety of protoxins and procarcinogens by way of its hydroperoxidase activity. Peroxidatic activation of acetaminophen and benzidine appears to involve the formation of a free radical intermediate which binds nucleophilic sites on macromolecules. The latter is proposed to initiate pathogenic effects. Prostaglandin H synthase is a potential alternative to mixed-function oxidase activation of chemicals which exert pathologic effects on the renal inner medulla.

Acetaminophen↗

PubMed1984

Renal cortical drug and xenobiotic metabolism following urinary tract obstruction.

Renal cortical metabolism of drugs and xenobiotics was assessed with microsomes prepared from normal, contralateral and 4-day postobstructive hydronephrotic kidneys. Microsomal mixed-function oxidase and prostaglandin H synthase systems were determined in control and 3-methylcholanthrene-treated rabbits. Cytochrome P450 content and biphenyl-4-hydroxylase activity but not cytochrome c reductase activity were reduced in the hydronephrotic kidney. 3-Methylcholanthrene treatment increased cytochrome P450 content and biphenyl-4-hydroxylase and acetanilide-4-hydroxylase activities in normal, contralateral, and hydronephrotic kidneys. However, even after 3-methylcholanthrene treatment, hydronephrotic kidney cytochrome P450 content and acetanilide-4-hydroxylase activity were not more than 20% of the corresponding normal kidney values. Prostaglandin H synthase metabolism of benzidine was observed in the hydronephrotic kidney but was at the limit of detection in normal or contralateral kidneys with or without 3-methylcholanthrene treatment. Characteristics of benzidine metabolism were consistent with the hydroperoxidase rather than the fatty acid cyclooxygenase activity of prostaglandin H synthase. Therefore, hydronephrosis alters the drug and xenobiotic metabolic profile of the renal cortex from a primarily mixed-function oxidase-dependent system to one with the potential for metabolism by the hydroperoxide component of prostaglandin H synthase.

Animals↗

PubMed1984

Inhibition by aspirin of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced bladder carcinogenesis and enhancement of forestomach carcinogenesis.

N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide (FANFT) is a potent urinary bladder carcinogen in the rat, and it can be metabolically activated in vitro by a variety of enzyme systems including aerobic cooxidation by prostaglandin H synthase. The latter enzyme is present in the rat bladder mucosa and can be inhibited by the oral administration of aspirin (ASA). To determine if ASA could inhibit the bladder carcinogenicity of FANFT, FANFT (0.2%) was co-administered in the diet with ASA (0.5%) for 12 weeks followed by 1 week of ASA only and then 56 weeks on control diet. 0.2% FANFT followed by control diet induced bladder carcinomas in 18 of 21 (87%) rats, but when ASA was co-administered, only 10 of 27 (37%) rats developed bladder carcinoma (p less than 0.001). However, forestomach tumors, not seen in rats fed only FANFT, developed in 7 rats fed FANFT plus ASA. No tumors occurred in control rats or those fed only ASA. Possible mechanisms, including the role of prostaglandin H synthase in FANFT metabolism, are discussed.

Animals↗

PubMed1984

Metabolic activation of the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide by prostaglandin H synthase.

It has been demonstrated that N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA), when fed with the diet, causes transitional carcinomas in rats. An important step in the mechanism of NFTA-induced carcinogenesis is endogenous metabolic activation to an ultimate carcinogen. We have proposed that the enzyme complex prostaglandin H synthase (PHS) is involved in the activation of certain renal and urinary tract carcinogens. This proposal was assessed by examining the activation of the 5-nitrofuran renal carcinogen NFTA and its deacetylated analogue 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) by PHS. Ram seminal vesicular and rabbit renal inner medullary microsomes were used as a source of PHS. Both NFTA and ANFT were activated by PHS to bind microsomal protein. Both microsomal preparations activated ANFT to bind DNA. However, only ram seminal vesicular microsomes activated NFTA to bind DNA. The rate of ANFT binding to macromolecules was considerably greater than NFTA with both microsomal preparations. Although activated ANFT was shown to bind several different homopolynucleotides, a preference for binding polyguanylic acid was demonstrated. Glutathione inhibition of carcinogen binding to macromolecules was shown to be due to the formation of a thioether conjugate. Deacetylation of NFTA was demonstrated in both tissues with deacetylation significantly exceeding acetylation of ANFT to NFTA in the kidney. Thus, renal PHS activation of both NFTA and ANFT was demonstrated with the rate of ANFT activation being considerably greater than NFTA. The conversion of NFTA to ANFT by intact tissue suggests that ANFT may contribute to NFTA renal carcinogenesis.

Acetylation↗

PubMed1984

Characterization of benzidinediimine: a product of peroxidase metabolism of benzidine.

[U-14C]Benzidine and unlabeled benzidine were used to synthesize benzidinediimine for which n.m.r., i.r. and u.v./visible spectra were obtained. Examination of benzidinediimine in acetate pH 4 buffer by electron spin resonance spectroscopy revealed that a free radical cation of benzidine was produced with maximum radical concentration occurring in 3-4 min. In contrast, u.v./visible spectroscopy revealed the production of a charge-transfer complex with maximum concentration occurring in 6-7 min. Liquid chromatography with electrical and radiochemical detection indicated that benzidine was the final product of benzidinediimine reduction in acetate buffer. The rate of reduction was greater at higher pH's and the time course for production of the free radical and charge-transfer complex did not coincide at any pH examined. Addition of DNA to [14C]benzidinediimine resulted in DNA labeling which was completely inhibited by glutathione. These data suggest that charge-transfer complex formation neither precedes nor coincides with free radical formation. They are consistent with the hypothesis that the free radical cation observed during peroxidatic oxidation of benzidine is derived from one-electron oxidation.

Benzidines↗

PubMed1984

Effect of PTH and 1,25(OH)2D3 on renal 25(OH)D3 metabolism, adenylate cyclase, and protein kinase.

The purpose of these studies was to characterize the action of PTH and 1,25(OH)2D3 on the renal metabolism of 25(OH)D3 to 1,25(OH)2D3 and 24,25(OH)2D3. Renal metabolism of 25(OH)D3, adenylate cyclase, and protein kinase activity were measured using isolated renal slices from rats fed a vitamin D-deficient, low-calcium diet and thyroparathyroidectomized. PTH added to renal slices for 4 h in vitro maximally increased 1,25(OH)2D3 production by 67% and decreased 24,25(OH)2D3 production by 24% over the concentration range 0.05-5.0 U/ml. Parathyroid hormone (PTH) (0.05 U/ml) added to renal slices for 5 min produced a significant increase in tissue cAMP and a near-maximal increase in cAMP-dependent protein kinase activity. Preincubation of renal slices with 50 nM 1,25(OH)2D3 decreased renal 1,25(OH)2D3 production by 26% and increased 24,25(OH)2D3 production by 55%. 1,25(OH)2D3 also blocked the effect of PTH (5.0 U/ml) on renal 25(OH)D3 metabolism. However, PTH-stimulated adenylate cyclase and protein kinase activity was not blocked by preincubation with 1,25(OH)2D3. These studies demonstrate that PTH may act directly on the kidney to modulate renal 25(OH)D3 metabolism and that this action can be inhibited by 1,25(OH)2D3. This inhibition by 1,25(OH)2D3 occurs at a site distal to or separate from PTH-stimulated protein kinase activity.

Adenylyl Cyclases↗

PubMed1984

Independent effects of bradykinin on adenosine 3',5'-monophosphate and prostaglandin E2 metabolism by rabbit renal medulla.

Bradykinin-stimulated increases in renal prostaglandin (PG) synthesis are thought to result in subsequent increases in cAMP content. This study assesses the relationship between bradykinin-stimulated increases in PGE2 and cAMP syntheses in renal inner medullary slices. Bradykinin-mediated increases in cAMP (2 min) preceded those in PGE2 (5 min) synthesis. Forskolin, an activator of adenylate cyclase, increased cAMP, while 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor, reduced cAMP. However, neither agent altered bradykinin-stimulated PGE2 synthesis. Aspirin decreased basal and abolished bradykinin-stimulated PGE2 production, but did not alter bradykinin-induced increases in cAMP content. Maximal stimulatory concentrations of 1-methyl-3-isobutylxanthine, a cyclic nucleotide phosphodiesterase inhibitor, and bradykinin were additive in their capacity to increase inner medullary cAMP content. These results suggest that 1-methyl-3-isobutylxanthine and bradykinin increase cAMP by separate mechanisms and that bradykinin increases inner medullary cAMP by a direct effect on the production of that cyclic nucleotide. Bradykinin-mediated increases in cAMP and PGE2 syntheses by renal medullary slices are independent effects of this renally acting hormone.

1-Methyl-3-isobutylxanthine↗

PubMed1984

Forskolin increases 1,25-dihydroxyvitamin D3 production by rat renal slices in vitro.

Renal production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] from 25-hydroxyvitamin D3 (25OHD3) is increased by PTH. The complete mechanism by which PTH modulates renal 25OHD3 metabolism is not known, but there is some evidence that the stimulation of renal cAMP production by PTH may be important. Therefore, we have used forskolin, a direct activator of adenylate cyclase in the intact tissue, to further investigate the role of cAMP in regulating renal 25OHD3 metabolism. The effect of forskolin on renal 25OHD3 metabolism and renal adenylate cyclase activity was measured using isolated renal slices from thyroparathyroidectomized rats previously fed a vitamin D-deficient, low calcium diet. Forskolin added to renal slices in vitro for 4 h increased renal 1,25-(OH)2-D3 production in a concentration-dependent manner. In separate experiments, forskolin was found to increase tissue cAMP in a concentration-dependent manner when added for 5 min. The concentration of forskolin necessary for half-maximal stimulation of adenylate cyclase was 10 microM, and that needed for half-maximal stimulation of 1,25-(OH)2-D3 production was 1 microM. PTH added to renal slices also increased renal 1,25-(OH)2-D3 production, but the effects of PTH and forskolin were not additive. Inclusion of 1,25-(OH)2-D3 in the incubation medium blocked the effect of forskolin on 1,25-(OH)2-D3 production, but it did not block the effect of forskolin on tissue cAMP content. These studies support the concept that forskolin and PTH modulate renal 25OHD3 metabolism though a cAMP-dependent pathway. However, this pathway may be further regulated at sites distal to cAMP production by compounds such as 1,25-(OH)2-D3.

Animals↗

PubMed1984

Effects of hypophysectomy and growth hormone treatment on renal hydroxylation of 25-hydroxycholecalciferol in rats.

Growth hormone stimulates intestinal calcium absorption. This action has been linked to vitamin D metabolism. We have investigated the effects of hypophysectomy and GH treatment on renal metabolism of 25-hydroxycholecalciferol (25-OH-D3). Renal hydroxylation of 25-OH-D3 was measured in vitro using the renal slice technique. Experiments were performed in young F344 rats fed a vitamin D-replete, low calcium diet for 4 weeks. In hypophysectomized rats, renal conversion of 25-OH-D3 to 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) was markedly reduced compared with sham-operated rats. Renal conversion of 25-OH-D3 to 24,25-(OH)2D3 was markedly increased in hypophysectomized rats compared with sham-operated rats. Treatment of hypophysectomized rats with rat GH (rGH) for 10 days resulted in a significant increase in renal conversion of 25-OH-D3 to 1,25-(OH)2D3 and a significant decrease in conversion to 24,25-(OH)2D3. Rat GH treatment caused no significant changes in serum levels of immunoreactive parathyroid hormone. Serum calcium concentrations were similar in all groups, and serum phosphorus was low in hypophysectomized rats. Treatment of hypophysectomized rats with ovine GH for 6 days caused changes which were much less pronounced than those induced by rGH. Renal conversion of 25-OH-D3 to 1,25-(OH)2D3 and 24,25-(OH)2D3 correlated well with growth rate (weight gain). These results suggest that GH, either directly or indirectly, modulates renal metabolism of 25-OH-D3.

24,25-Dihydroxyvitamin D 3↗

PubMed1984

Antithyroid drugs interact with renal medullary prostaglandin H synthase.

The antithyroid drugs propylthiouracil and methimazole exert their effects on the thyroid gland by inhibiting thyroid peroxidase. In addition to this effect, these drugs have been reported to inhibit prostaglandin production in both the thyroid gland and the kidney. The purpose of our studies was to evaluate the mechanism of the effects of these drugs on prostaglandin production. Both propylthiouracil and methimazole reversibly inhibited prostaglandin E2 production in both inner medullary slices and isolated renal papillary collecting tubule cells. The inhibition of arachidonic acid-induced increases in PGE2 production indicated that the effects of methimazole and propylthiouracil were on the enzyme complex prostaglandin H synthase, and not on the phospholipase mechanisms responsible for the release of arachidonic acid from tissue phospholipids. Propylthiouracil inhibited both arachidonic acid and hydrogen peroxide-dependent binding of 14C-N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide to protein, indicating that the effect of propylthiouracil is on the hydroperoxidase and not on the cyclooxygenase component of prostaglandin H synthase. Our data also indicate the potential of the antithyroid drugs for inhibition of metabolism of drugs and xenobiotics by prostaglandin H synthase. Metabolism of both methimazole and propylthiouracil by the hydroperoxidase component of prostaglandin H synthase was demonstrated. It is proposed that this interaction with the hydroperoxidase component of prostaglandin H synthase is at least in part the mechanism by which propylthiouracil and methimazole inhibit prostaglandin production. The inhibition of tissue peroxidase provides these agents with the capability to prevent the peroxidatic metabolism of drugs and xenobiotics.

Animals↗